Compounds of formula I are described in EP 0 627 406 as medicaments for immunosuppression, suppressing rejection, autoimmune diseases, rheumatoid arthritis, psoriasis, atopic dermatitis, bronchial asthma, pollinosis or Behcet's disease.
Pain is a complex subjective sensation reflecting real or potential tissue damage and the affective response to it. Acute pain is a physiological signal indicating a potential or actual injury. Chronic pain can either be somatogenic (organic) or psychogenic. Chronic pain is frequently accompanied or followed by vegetative signs, which often result in depression.
Somatogenic pain may be of nociceptive origin, inflammatory or neuropathic. Nociceptive pain is judged to be commensurate with ongoing activation of somatic or visceral pain-sensitive nerve fibers. Neuropathic pain results from dysfunction in the nervous system; it is believed to be sustained by aberrant somatosensory processes in the peripheral nervous system, the central nervous system (CNS), or both. (For an overview of pain mechanisms, see, for example, Scholz and Woolf, 2002; Julius and Basbaum, 2001, Woolf and Mannion, 1999; Wood, J. D., 2000; Woolf and Salter, 2000.)
Chronic pain results in individual suffering and social economic costs of tremendous extent. Existing pharmacological pain therapies are widely unsatisfying both in terms of efficacy and of safety.
Up to now, two classes of analgesics were mainly employed for the treatment of pain: Non-opioid analgesics, mostly acetaminophen and NSAIDS (non-steroidal anti-inflammatory drugs) and opioid (narcotic) agonists (wherein “opioid” is a generic term for natural or synthetic substances that bind to specific opioid receptors in the CNS, producing an agonist action). Unfortunately both analgesic classes, opioids and non-opioids, have several unwanted side effects. The most serious side effects of opioids are the possibility of inhibition of the respiratory system and, after long-term treatment, the possibility of addiction (Schaible H. G., Vanegas H.: How do we manage chronic pain? Baillieres Best. Pract. Res. Clin. Rheumatol. 2000 December; 14(4):797-811). NSAIDs, a major class of non-opioids, on the other hand, can induce a variety of gastrointestinal complications such as ulcers and bleeding, but also kidney damage (Schaible H. G., Vanegas H., 2000). It has been estimated that, in the U.S.A., about 16,000 patients die every year because of severe gastro-intestinal complications caused by conventional NSAIDs.
In light of the severe drawbacks connected with state of the art pain treatments, there is a great need for novel classes of pain modulating drugs. Especially in light of the vast gap between the fast advancing understanding of the neurobiology of pain and the unmet clinical need to provide effective treatments without the drawbacks of state of the art treatments, efforts need to be directed to the discovery of new targets for novel classes of analgesics.
It was found that sphingosine-1-phosphate (S1P) is involved in nociceptive processing and is able to decrease pain. S1P is able to interact with at least one S1P receptor, activates the receptor and lowers intracellular cyclicadenosine mono phosphate (AMP). S1P can bind to a family of five G-Protein-coupled receptors, S1P1-5, also known as Endothelial Differentiation Gene receptor EDG 1, 3, 5, 6 and 8. Members of the S1P-receptor family regulate functions involved in neural cell morphology, tumor cell invasiveness, cell proliferation, angiogenesis, vascular maturation, and inhibition of neutrophil motility and migration (Kluk M. J. and Hla T. (2002), Biochim Biophys Acta 1582, 72-80; Spiegel S, and Milstien S. (2002), J Biol Chem 277, 25851-25854). It is well known that several of these actions are mediated at least in part by the inhibition of cAMP synthesis. S1P achieves its adenylate cyclase (AC) inhibitory actions by activating PAM and the inhibitory G-protein Gi. S1P treatment results in a change of the cellular localization of PAM and inhibition of AC enzyme activity. The compounds of formula I and S1P are both S1P-receptor agonists. Therefore, the compounds of formula I can be used for treatment of pain.